Live attenuated bivalent ca influenza A virus reassortant vaccine was less immunogenic in the elderly than inactivated influenza A virus vaccine. Little increase in immunogenicity was observed when parenterally administered inactivated vaccine was used in combination with live, bivalent ca influenza A virus vaccine administered intranasally. During the course of these studies we observed that the elderly have non-hemagglutination-inhibiting (HAI) antibodies that correlate with resistance to infection with live virus vaccines. Cold-adapted (ca) and avian-human (ah) influenza A/Bethesda/85 (H3N2) reassortant virus vaccines were observed to be both safe and immunogenic in seronegative infants and children. However, the ah, but not ca, reassortant A/Kawasaki/86 (H1N1) virus caused a febrile response in one fourth of seronegative infants and children. Thus, the influenza virus hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins can significantly affect the level of attenuation specified by the six avian influenza A donor virus genes that code for the non-surface viral proteins. In contrast, the 6 genes of the influenza A/AA/6/60 ca donor virus that code for the non-surface viral proteins are able to confer a satisfactory level of attenuation upon reassortant viruses bearing either the H1N1 or H3N2 surface glycoproteins of wild type human influenza A virus. The influenza B/AA/186 ca reassortant virus was safe, highly infectious, phenotypically stable, immunogenic, and non-transmissible in seronegative infants.